A Quantitative Assessment Of Tks5 SH3 Domain Function On Invadopodia Development And Activity

ASU Author/Contributor (non-ASU co-authors, if there are any, appear on document)
Brewer Douglas Logan (Creator)
Appalachian State University (ASU )
Web Site: https://library.appstate.edu/
Darren F. Seals

Abstract: When cancer cells move out of their tissue of origin to other body locations as part of metastatic disease, patient morbidity and mortality declines. Thus, combating metastasis is perhaps the most significant therapeutic challenge in cancer. Some cancer cells invade foreign tissues by creating actin-rich structures that focalize proteolytic degradation of the extracellular matrix called invadopodia. Catalyzing invadopodia development is the scaffolding protein and Src tyrosine kinase substrate Tks5. Previous research suggests that both Src and Tks5 are necessary and sufficient for invadopodia formation, and that their expression correlates with tumor growth, angiogenesis, and metastasis. However, relatively little is known about the five, protein-binding SH3 domains of Tks5. In the LNCaP prostate carcinoma cell line, ectopic expression of Tks5 constructs harboring inactivating mutations in any one of the first three SH3 domains accentuated invadopodia development and their matrix degrading capabilities. However, when these constructs were transfected into invadopodia-competent Src-transformed NIH3T3 (Src3T3) cells, invadopodia formation and matrix degradation were disrupted in dominant-negative fashion. Here I have used sophisticated measurements of invadopodia numbers, invadopodia marker protein localization at high magnification, and quantitative measurement of matrix degradation among individually transfected cells to highlight the remarkable disparity of these results across the different cancer cell lines. Based on these results, I hypothesize that Tks5 acts in either a closed (inactive) or open (active) conformation. Src-dependent Tks5 phosphorylation is expected to disrupt these putative intramolecular interactions and create an open conformation suitable for the binding of other proteins involved in invadopodia development.

Additional Information

Logan, B. (2020). A Quantitative Assessment Of Tks5 SH3 Domain Function On Invadopodia Development And Activity. Unpublished Master’s Thesis. Appalachian State University, Boone, NC.
Language: English
Date: 2020
Cancer Metastasis, Tks5, Invadopodia Podosomes, SH3 domains, Cancer activity

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